Magnetoresistive sensor array for molecule detection and related detection schemes

ABSTRACT

A sensing device comprises a plurality of magnetoresistive (MR) sensors, at least one fluidic channel, and detection circuitry coupled to the MR sensors. Each MR sensor is configured to detect the presence of molecules (e.g., biologic molecules) labeled by magnetic nanoparticles (MNPs). The sensors are encapsulated by an insulating material that protects the sensors from the contents of the at least one fluidic channel. The insulating material has a surface within the fluidic channel that provides sites for binding the molecules to be detected. The detection circuitry is configured to detect (a) a characteristic of magnetic noise of each MR sensor, the characteristic being influenced by a presence or absence of one or more MNPs at each site, or (b) a change in resistance, current, and/or voltage drop of each MR sensor, wherein the change is influenced by the presence or absence of one or more MNPs at each site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and hereby incorporates byreference, for all purposes, the entirety of the contents of U.S.Provisional Application No. 62/833,237, filed Apr. 12, 2019 and entitled“MAGNETORESISTIVE SENSOR ELEMENTS FOR NUCLEIC ACID SEQUENCING ARRAYS ANDDETECTION SCHEMES FOR NUCLEIC ACID SEQUENCING.”

BACKGROUND Field of the Disclosure

Embodiments of the present disclosure generally relate tomagnetoresistive (MR) sensor arrays for detection of molecules coupledto magnetic nanoparticles (MNPs), such as for nucleic acid sequencingsuch as deoxyribonucleic acid (DNA) sequencing, and methods of usingsuch MR sensor arrays for molecule detection.

Description of the Related Art

Current state-of-the-art sequencing systems are based on fluorescencesignal detection and provide throughputs of 20 billion reads per run(https://www.illumina.com/systems/sequencing-platforms/novaseq.html).Achieving such performance requires large-area flow cells,high-precision free-space imaging optics, and expensive high-powerlasers to generate sufficient fluorescence signals for successful basedetection.

Gradual increases in sequencing by synthesis (SBS) throughput have beenaccomplished in two ways, the first being an outward scaling where thesize and the number of flow cells in the sequencers is increased. Thisapproach increases both the cost of reagents and the price of thesequencing system as more high-power lasers and high-precisionnano-positioners must be employed. The second approach involves inwardscaling where the density of DNA testing sites is increased so that thetotal number of sequenced DNA strands in a fixed-size flow cell ishigher. To do so, increasingly higher numerical aperture (NA) lensesmust be employed to distinguish the signal from neighboring fluorophoresas the spacing decreases. However, this approach cannot be implementedindefinitely as the Rayleigh criterion puts the distance betweenresolvable light point sources at 0.61λ/NA, constraining the minimumdistance between two sequenced DNA strands to be no smaller than ˜400nm. Similar resolution limits apply to sequencing directly on top ofimaging arrays (similar to cell phone cameras) where the smallest pixelsize achieved so far is ˜1 μm(https://www.ephotozine.com/article/complete-guide-to-image-sensor-pixel-size-29652).

The Rayleigh criterion currently represents the fundamental limitationfor inward scaling of optical SBS systems which can only be overcome byapplying super-resolution imaging techniques (see A. M. Sydor, K. J.Czymmek, E. M. Puchner, and V. Mannella, “Super-Resolution Microscopy:From Single Molecules to Supramolecular Assemblies”, Special Issue:Quantitative Cell Biology, Vol. 25, 730, 2015) and has not yet beenachieved in highly multiplexed systems. Hence, increasing throughput anddecreasing cost of optical SBS sequencers has been slow due to the needto build bigger flow cells and implement more expensive optical scanningand imaging systems.

Therefore, there is a need for new and improved apparatuses for andmethods of detecting the presence of molecules such as nucleic acidsthat overcome the limitations of conventional apparatuses and methods.

SUMMARY

This summary represents non-limiting embodiments of the disclosure.

Disclosed herein are apparatuses and methods of using magnetic particlesand magnetic sensors, such as magnetoresistive (MR) sensors, to performmolecule detection, such as for nucleic acid sequencing (e.g., DNAsequencing using SBS chemistry methods).

In some embodiments, a sensing device comprises at least one fluidicchannel configured to receive a plurality of molecules to be detected,wherein at least some of the plurality of molecules are coupled torespective magnetic nanoparticles (MNPs), a plurality ofmagnetoresistive (MR) sensors, an insulating material encapsulating theplurality of MR sensors and for providing a barrier between theplurality of MR sensors and a contents of the at least one fluidicchannel, and detection circuitry coupled to each of the plurality of MRsensors. In such embodiments, a surface of the insulating materialwithin the fluidic channel provides a plurality of sites for binding theplurality of molecules to be sequenced, of the plurality of sites beinglocated among the plurality of MR sensors, and the detection circuitryis configured to detect a characteristic of a magnetic noise of each ofthe plurality of MR sensors in response to a presence or absence of oneor more magnetic nanoparticles (MNPs) at each of the plurality of sites,wherein the characteristic of the magnetic noise is influenced by thepresence or absence of one or more MNPs at each of the plurality ofsites. The characteristic of the magnetic noise may be an amplitude ofthe magnetic noise at a particular frequency or within a particularfrequency band, a fluctuation of the magnetic noise, or a phase of themagnetic noise.

In some embodiments, one or more of the MR sensors comprises a pinnedlayer, a free layer, and a spacer layer disposed between the pinnedlayer and the free layer. The pinned layer or the free layer maycomprise one or more ferromagnetic (FM) layers. The spacer layer maycomprise an insulating layer or a metal layer, or both an insulatinglayer and a metal layer. In some embodiments, absent an applied magneticfield and absent the presence of one or more MNPs, an orientation of amagnetic moment of the free layer is approximately 90° from anorientation of a magnetic moment of the pinned layer.

In some embodiments in which the characteristic of the magnetic noise isan amplitude of the magnetic noise at a particular frequency or within aparticular frequency band, the detection circuitry comprises a biaselement coupled to at least one of the plurality of MR sensors andconfigured to generate a bias across the at least one of the pluralityof MR sensors, a first low pass filter and amplifier combination coupledto the at least one of the plurality of MR sensors to filter and amplifya signal from the at least one of the plurality of MR sensors, areference oscillator configured to generate a reference signal having aparticular frequency chosen to maximize a change in the signal at theparticular frequency when at least one of the one or more MNPs labelinga particular molecule type is detected by the at least one of theplurality of MR sensors at one or more of the plurality of sites, amixer coupled to the reference oscillator and an output of the first lowpass filter and amplifier combination, wherein the mixer is configuredto mix an output signal from the first low pass filter and amplifiercombination with the reference signal, a second low pass filter andamplifier combination coupled to the mixer, and an envelope detectorconfigured to receive an output signal from the second low pass filterand amplifier combination and provide a signal for detection, wherein avoltage of the signal for detection is proportional to the amplitude ofthe magnetic noise.

In some embodiments in which the characteristic of the magnetic noise isa fluctuation of the magnetic noise, the detection circuitry comprises abias element coupled to at least one of the plurality of MR sensors andconfigured to generate a bias across the at least one of the pluralityof MR sensors, an amplifier coupled to the at least one of the pluralityof MR sensors to filter and amplify a signal from the at least one ofthe plurality of MR sensors, a filter coupled to the amplifier, and anenvelope detector configured to receive an output signal from the filterand provide a signal for detection, wherein a voltage of the signal fordetection is proportional to the fluctuation of the magnetic noise.

In some embodiments in which the characteristic of the magnetic noise isa phase of the magnetic noise, the detection circuitry comprises a phaselocked loop configured to provide an error signal output thatcorresponds to the phase of the magnetic noise.

In some embodiments, the sensing device further comprises a plurality oflines coupled to the plurality of MR sensors, and a plurality ofselector elements, each of the plurality of selector elements coupled toat least one of the plurality of lines and to a respective one of theplurality of MR sensors. In some embodiments, the plurality of selectorelements comprises a transistor. In some embodiments, the plurality ofselector elements comprises an in-stack selector element.

In some embodiments, the sensing device is a sequencing device, and themolecules are biologic molecules (e.g., nucleic acid molecules).

In some embodiments, a first subset of the plurality of MR sensors isarranged in a first row, a second subset of the plurality of MR sensorsis arranged in a second row, the second row being substantially parallelto the first row, and the at least one fluidic channel is disposedbetween the first and second rows.

In some embodiments, the sensing device further comprises a selectorelement, such as a transistor or an in-stack selector element.

In some embodiments, the sensing device further comprises a magneticcomponent configured to apply a magnetic field across the sensingdevice. The magnetic component may be, for example, an electromagnet, adistributed coil, a solenoid, a permanent magnet, a super-conductingmagnet, or a combination thereof.

In some embodiments, a method of using the sensing device comprisesapplying a magnetic field across the sensing device, and detecting, bythe detection circuitry, the characteristic of the magnetic noise ofeach of the plurality of MR sensors. In some such embodiments, in avicinity of each of the plurality of MR sensors, the applied magneticfield is (a) in a substantially same direction as a field emanating fromthe one or more MNPs, or (b) in a substantially opposite direction fromthe field emanating from the one or more MNPs.

In some embodiments, at least one of the MR sensors comprises a pinnedlayer, a free layer, and a spacer layer disposed between the pinnedlayer and the free layer, and an orientation of a magnetic moment of thefree layer is approximately 90° from an orientation of a magnetic momentof the pinned layer, and a method of fabricating the sensing devicecomprises at least one of: applying a hard bias field; patterning the atleast one of the MR sensors into a rectangle or ellipse; etching thefree and pinned layers along an axis to induce texturing; or usingperpendicular magnetic anisotropy to pull the free layer out of planewhile keeping the pinned layer in the plane of the at least one of theMR sensors.

In some embodiments, a sensing device comprises at least one fluidicchannel configured to receive a plurality of molecules to be detected,wherein at least some of the plurality of molecules to be detected arecoupled to respective magnetic nanoparticles (MNPs), a plurality ofmagnetoresistive (MR) sensors, an insulating material encapsulating theplurality of MR sensors and for providing a barrier between theplurality of MR sensors and a contents of the at least one fluidicchannel, and detection circuitry coupled to each of the plurality of MRsensors. In some such embodiments, a surface of the insulating materialwithin the fluidic channel provides a plurality of sites for binding theplurality of molecules to be detected, the plurality of sites beinglocated among the plurality of MR sensors, and the detection circuitryis configured to detect a change in resistance, current, and/or voltagedrop across each of the plurality of MR sensors, wherein the change inresistance, current, and/or voltage drop is influenced by the presenceor absence of one or more MNPs at each of the plurality of sites.

In some embodiments, the detection circuitry is further configured toreport the change in resistance, current, and/or voltage drop as abinary output that indicates the presence or absence of a particular MNPlabeling a particular molecule type at each of the plurality of sites.

In some embodiments, the detection circuitry is further configured toreport the change in resistance, current, or voltage drop at each of theplurality of sites as a quantized output having one of a plurality oflevels, at least some of the levels being used to differentiate MNPshaving different saturation magnetizations, with each saturationmagnetization corresponding to a particular MNP labeling a particularmolecule type.

In some embodiments, the sensing device further comprises a plurality oflines coupled to the plurality of MR sensors, and a plurality ofselector elements, each of the plurality of selector elements coupled toat least one of the plurality of lines and to a respective one of theplurality of MR sensors. In some embodiments, the plurality of selectorelements includes a transistor. In some embodiments, the plurality ofselector elements is an in-stack selector element.

In some embodiments, the sensing device is a sequencing device, and themolecules are biologic molecules (e.g., nucleic acid molecules).

In some embodiments, each of the MR sensors comprises a pinned layer, afree layer, and a spacer layer disposed between the pinned layer and thefree layer, and, absent an applied magnetic field and absent thepresence of one or more MNPs, an orientation of a magnetic moment of thefree layer is approximately 90° from an orientation of a magnetic momentof the pinned layer.

In some embodiments, a first subset of the plurality of MR sensors isarranged in a first row, a second subset of the plurality of MR sensorsis arranged in a second row, the second row being substantially parallelto the first row, and the at least one fluidic channel is disposedbetween the first and second rows.

In some embodiments, the sensing device further comprises a selectorelement. In some embodiments, the selector element comprises atransistor. In some embodiments, the selector element is an in-stackselector element.

In some embodiments, at least one of the MR sensors comprises a pinnedlayer, a free layer, and a spacer layer disposed between the pinnedlayer and the free layer, and an orientation of a magnetic moment of thefree layer is approximately 90° from an orientation of a magnetic momentof the pinned layer, and a method of fabricating the sensing devicecomprises at least one of: applying a hard bias field; patterning the atleast one of the MR sensors into a rectangle or ellipse; etching thefree and pinned layers along an axis to induce texturing; or usingperpendicular magnetic anisotropy to pull the free layer out of planewhile keeping the pinned layer in the plane of the at least one of theMR sensors.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above-recited features of the presentdisclosure can be understood in detail, a more particular description ofthe disclosure is provided in reference to embodiments, some of whichare illustrated in the appended drawings. It is to be noted, however,that the appended drawings illustrate only typical embodiments of thisdisclosure and are therefore not to be considered limiting of its scope,for the disclosure may admit to other equally-effective embodiments.Objects, features, and advantages of the disclosure will be readilyapparent from the following description of certain embodiments taken inconjunction with the accompanying drawings in which:

FIG. 1 illustrates a portion of a magnetic sensor in accordance withsome embodiments.

FIGS. 2A, 2B, and 2C illustrate the basic construction of amagnetoresistive (MR) device and how it can be used as a magnetic sensorin accordance with some embodiments.

FIGS. 3A and 3B illustrate the relationship between the resistance ofthe exemplary magnetic sensor illustrated in FIG. 1 and the anglebetween the moments of its two ferromagnetic layers in accordance withsome embodiments.

FIGS. 4A, 4B, and 4C illustrate an apparatus for molecule detection inaccordance with some embodiments.

FIGS. 5A, 5B, 5C, and 5D illustrate portions of an exemplary apparatusthat includes several channels in accordance with some embodiments.

FIG. 5E illustrates a magnetic sensor selection approach in accordancewith some embodiments.

FIG. 5F illustrates another magnetic sensor selection approach inaccordance with some embodiments.

FIG. 6 is a flowchart illustrating a method of manufacturing anapparatus for molecule detection in accordance with some embodiments.

FIG. 7 illustrates the results of each step of the method ofmanufacturing illustrated in FIG. 6, with a final panel showing apolymerase bound to the edge of a magnetic sensor to be used to captureintroduced nucleic acid bases such as DNA bases in accordance with someembodiments.

FIGS. 8A, 8B, and 8C illustrate a cross-point array architecture of MRsensor elements in accordance with some embodiments.

FIGS. 9A and 9B illustrate a magnetic sensor and detection using thatmagnetic sensor in accordance with some embodiments.

FIG. 10A is a detection circuit in accordance with some embodiments.

FIG. 10B is another detection circuit in accordance with someembodiments.

FIG. 11 is another detection circuit in accordance with someembodiments.

To facilitate understanding, identical reference numerals have beenused, where possible, to designate identical elements that are common tothe figures. It is contemplated that elements disclosed in oneembodiment may be beneficially utilized on other embodiments withoutspecific recitation.

DETAILED DESCRIPTION

In the following, reference is made to embodiments of the disclosure. Itshould be understood, however, that the disclosure is not limited tospecific described embodiments. Instead, any combination of thefollowing features and elements, whether related to differentembodiments or not, is contemplated to implement and practice thedisclosure. Furthermore, although embodiments of the disclosure mayachieve advantages over other possible solutions and/or over the priorart, whether or not a particular advantage is achieved by a givenembodiment is not limiting of the disclosure. Thus, the followingaspects, features, embodiments and advantages are merely illustrativeand are not considered elements or limitations of the appended claimsexcept where explicitly recited in a claim(s). Likewise, reference to“the disclosure” shall not be construed as a generalization of anyinventive subject matter disclosed herein and shall not be considered tobe an element or limitation of the appended claims except whereexplicitly recited in a claim(s).

The terms “over,” “under,” “between,” “on,” and other similar terms asused herein refer to a relative position of one layer with respect toother layers. As such, for example, one layer disposed over or underanother layer may be directly in contact with the other layer or mayhave one or more intervening layers. Moreover, one layer disposedbetween layers may be directly in contact with the two layers or mayhave one or more intervening layers. In contrast, a first layer “on” asecond layer is in contact with the second layer. The relative positionof the terms does not define or limit the layers to a vector spaceorientation of the layers.

The term “coupled” is used herein to refer to elements that are eitherdirectly connected or connected through one or more interveningelements. For example, as explained below a line (e.g., for selecting orreading a characteristic of a magnetic sensor) may be directly connectedto a magnetic sensor, or it may be connected via intervening elements.

It is to be understood that the disclosures herein may be used to detectany type of molecule to which a magnetic particle can be attached. Inother words, any molecule type that can be labeled by a magneticnanoparticle may be detected using the sensing devices disclosed herein.Such molecule types may be biologic molecule types, such as proteins,antibodies, etc. For example, the disclosures herein may be used todetect nucleic acids (e.g., in DNA sequencing). The disclosures hereinmay also be used to detect non-biologic (inorganic or non-living)molecules, such as contaminants, minerals, chemical compounds, etc. Thepresentation of the disclosure in the context of nucleic acid sequencingis solely exemplary and is not intended to limit the scope of thepresent disclosure.

Furthermore, although the description herein focuses on DNA as anexemplary nucleic acid, the various embodiments described can be appliedto nucleic acid sequencing in general. Similarly, although SBS is usedfor illustrative purposes in the following description, the variousembodiments are not so limited to SBS sequencing protocols (e.g.,dynamic sequencing could be used instead).

Disclosed herein are apparatuses and methods to use magnetic particlesand magnetic sensors to perform detection of molecules, such as innucleic acid sequencing (e.g., DNA sequencing using SBS chemistrymethods). Specifically, embodiments of this disclosure are directed tovarious magnetoresistive (MR) device embodiments that can be used asmagnetic field detectors. Embodiments of the present disclosure alsoinclude various detection methods to measure characteristics of themagnetic sensors and/or variations in the magnetic sensorcharacteristics in response to a magnetic field from a magneticnanoparticle label.

In some embodiments, an apparatus for molecule detection comprises anarray of magnetic sensors. Each of the magnetic sensors of the magneticsensor array may be a thin-film device that uses the MR effect (e.g., itmay be a MR sensor) to detect magnetic nanoparticles (MNPs) in a fluidicchannel of the apparatus. Each magnetic sensor may operate as apotentiometer with a resistance that varies as the strength and/ordirection of the sensed magnetic field changes. Each magnetic sensor mayhave dimensions of less than about 30 nm to detect magnetic fields onthe order of a few millitesla (mT).

FIG. 1 illustrates a portion of a magnetic sensor 105 in accordance withsome embodiments. The exemplary magnetic sensor 105 of FIG. 1 has abottom portion 108 and a top portion 109 and comprises three layers,e.g., two ferromagnetic layers 106A, 106B separated by a nonmagneticspacer layer 107. The nonmagnetic spacer layer 107 may be, for example,a metallic material or combination of metallic materials, such as, forexample, copper or silver, in which case the structure is called a spinvalve (SV), or it may be an insulator such as, for example, alumina ormagnesium oxide, in which case the structure is referred to as amagnetic tunnel junction (MTJ). Suitable materials for use in theferromagnetic layers 106A, 106B include, for example, alloys of Co, Ni,and Fe (sometimes mixed with other elements). The example materialsdescribed above are merely exemplary and are not intended to belimiting. Materials suitable for use in MTJs are known to those havingordinary skill in the art.

In some embodiments, the magnetic sensor 105 is a thin-film device, andthe ferromagnetic layers 106A, 106B are engineered to have theirmagnetic moments oriented either substantially in the plane of the filmor substantially perpendicular to the plane of the film. Additionalmaterials may be deposited below and/or above the three layers 106A,106B, and 107 shown in FIG. 1 to serve purposes such as interfacesmoothing, texturing, and protection from processing used to pattern theapparatus 100 (shown and described in the context of, e.g., FIGS. 4A,5A, etc.), but the active region of the magnetic sensor 105 lies in thetrilayer structure shown in FIG. 1. Thus, a component that is in contactwith a magnetic sensor 105 may be in contact with one of the threeillustrated layers 106A, 106B, or 107, or it may be in contact withanother part of the magnetic sensor 105 that is not illustrated in FIG.1.

To understand how a MR device works, consider how an electron in anelectric current interacts with a thin film ferromagnetic (FM) layer.Quantum mechanics dictate that the probability is high that an electroninteracting with the FM layer will cause the electron spin to beoriented preferentially parallel or antiparallel to the direction of themagnet's moment for transmitted and reflected electrons respectively, asshown in FIG. 2A. Electrons with spin parallel to the moment 206 of theFM layer 204 preferentially pass through the FM layer 204 (spin 210),whereas those with spin antiparallel preferentially are reflected back(spin 208). Due to this phenomenon, the interface between a nonmagnetic(NM) layer 202 (assumed for purposes of this explanation to be a metallayer) and a FM layer 204 acts as a spin filter that can act to spinpolarize (i.e., make one spin direction more preferential) an incomingelectric current.

For a device with two FM layers 224 and 228 separated by a nonmagneticmetal layer 226 (spacer layer) as shown in FIGS. 2B and 2C, an incomingelectric current spin polarized by the first FM layer (FM1) 224interacts differently with the second FM layer (FM2) 228, depending onthe orientation of that layer's magnetic moment. If the moments of bothFM layers 224 and 228 are parallel to one another (FIG. 2B), then manyelectrons will pass through the device because many electrons in thecurrent will have their spin oriented with the moment of the second FM228 (spin 234). Few electrons will be reflected back (spin 232).

In the opposite case, where the moments of the two FM layers 224 and 228are oriented in an anti-parallel fashion (FIG. 2C), many electrons willbe blocked from passing through the second FM layer 228 (spin 236), andfar fewer electrons will traverse the device (spin 238). This means theamount of current passing through the device is dependent on theorientation of the two FM layers 224 and 228 with respect to oneanother. Because the resistance of the device is proportional to thecurrent, the resistance of the device is dependent on the orientation ofthe moments (i.e., the resistance is smaller when the moments areparallel than it is when they are antiparallel).

Whereas the above description presumes use of a nonmagnetic metal spacerlayer 226 separating the two FM layers 224 and 228, (a configurationalso known as a spin valve (SV) or giant magnetoresistance (GMR)device), an insulating layer known as a tunneling barrier canalternatively be used as the spacer layer separating the FM layers. Insuch implementations, the spacer layer may be made of oxide-basedmaterial. These types of devices are called magnetic tunnel junctions(MTJs), and they exhibit a similar resistance response (referred to astunnel magnetoresistance or TMR) because of spin polarized tunneling asopposed to spin filtering.

MR devices have been used in many applications, including magneticrecording, magnetic field sensing, and magnetic memory. In these cases,it is usually preferable to design the MR device to have one FM layer beeffectively “pinned” so that the direction in which its moment points instays fixed and is not easily altered by the application of a magneticfield. This is usually achieved by placing an antiferromagnetic (AFM)layer adjacent to the pinned layer and using an effect called exchangecoupling that provides strong unidirectional anisotropy for the FMlayer's moment. The second FM layer is left “free” to rotate under theimpulse of a magnetic field such that its moment rotates with respect tothe fixed orientation of the pinned FM layer so that the resistance ofthe device becomes a detector of the magnetic field direction oramplitude by effectively acting as a magnetic field to voltagetransducer.

Magnetoresistance can be defined as

${{MR} = {R_{0} + {\Delta\; R\;{\sin^{2}\left( \frac{\theta}{2} \right)}}}},$where R₀ is the resistance of the device when the moments are orientedin a parallel configuration, ΔR is the difference between resistance inparallel and antiparallel orientations, and θ is the angle between thetwo moments. For magnetic field sensing applications, a linear responseto the magnetic field is desired from the sensor. Considering theequation above, the sensor should ideally be designed and fabricated tohave the two FM layers oriented approximately 90° with respect to oneanother. This may be achieved by exchange biasing the pinned layer withan anti-ferromagnet and using a “hard bias” coating to rotate the freelayer approximately 90° away from the pinned layer. Further detail onthis design, as applied to embodiments related to sequencingapplications, will be given below.

FIGS. 3A and 3B illustrate the resistance of MR sensors, which isproportional to 1-cos(θ), where θ is the angle between the moments ofthe two ferromagnetic layers 106A, 106B shown in FIG. 1. To maximize thesignal generated by a magnetic field and provide a linear response ofthe magnetic sensor 105 to an applied magnetic field, the magneticsensors 105 may be designed such that the moments of the twoferromagnetic layers 106A, 106B are oriented π/2 or 90 degrees withrespect to one another in the absence of a magnetic field. Thisorientation can be achieved by any number of methods that are known inthe art. As discussed above, one solution is to use an antiferromagnetto “pin” the magnetization direction of one of the ferromagnetic layers(either 106A or 106B, designated as “FM1”) through an effect calledexchange biasing and then coat the sensor with a bilayer that has aninsulating layer and permanent magnet. The insulating layer avoidselectrical shorting of the magnetic sensor 105, and the permanent magnetsupplies a “hard bias” magnetic field perpendicular to the pinneddirection of FM1 that will then rotate the second ferromagnet (either106B or 106A, designated as “FM2”) and produce the desiredconfiguration. Magnetic fields parallel to FM1 then rotate FM2 aboutthis 90 degree configuration, and the change in resistance results in avoltage signal that can be calibrated to measure the field acting uponthe magnetic sensor 105. In this manner, the magnetic sensor 105 acts asa magnetic-field-to-voltage transducer.

Note that although the example discussed immediately above described theuse of ferromagnets that have their moments oriented in the plane of thefilm at 90 degrees with respect to one another, a perpendicularconfiguration can alternatively be achieved by orienting the moment ofone of the ferromagnetic layers 106A, 106B substantially out of theplane of the film, which may be accomplished using what is referred toas perpendicular magnetic anisotropy (PMA).

The magnetic sensors 105 may be incorporated into an apparatus for thedetection of molecules that are coupled to respective magneticnanoparticles (e.g., for nucleic acid sequencing). FIGS. 4A, 4B, and 4Cillustrate an apparatus 100 that may be used, e.g., for nucleic acidsequencing in accordance with some embodiments. FIG. 4A is a top view ofthe apparatus, and FIG. 4B is a cross-section view at the positionindicated in FIG. 4A. FIG. 4C is a block diagram showing components ofthe apparatus 100. As shown in FIGS. 4A and 4C, the apparatus 100comprises a magnetic sensor array 110 that includes a plurality ofmagnetic sensors 105, with four magnetic sensors 105A, 105B, 105C, and105D shown in FIG. 4A. (For simplicity, this document refers generallyto the magnetic sensors by the reference number 105. Individual magneticsensors are given the reference number 105 followed by a letter.) Themagnetic sensor array 110 shown in the exemplary embodiment of FIG. 4Ais a linear array.

In some embodiments, each of the plurality of magnetic sensors 105 iscoupled to at least one line 120 for reading a characteristic of one ormore of the magnetic sensors 105 (e.g., an amplitude of the magneticnoise at a particular frequency or within a particular frequency band, afluctuation of the magnetic noise, a phase of the magnetic noise, and/ora change in resistance, current, and/or voltage drop across the magneticsensor 105). (For simplicity, this document refers generally to thelines by the reference number 120. Individual lines are given thereference number 120 followed by a letter.) In the exemplary embodimentshown in FIG. 4A, each magnetic sensor 105 of the magnetic sensor array110 is coupled to two lines 120. Specifically, the magnetic sensor 105Ais coupled to the lines 120A and 120E, the magnetic sensor 105B iscoupled to the lines 120B and 120E, the magnetic sensor 105C is coupledto the lines 120C and 120E, and the magnetic sensor 105D is coupled tothe lines 120D and 120E. The lines 120A, 120B, 120C, and 120D resideunder the magnetic sensors 105A, 105B, 105C, and 105D, respectively, andthe line 120E resides over the magnetic sensors 105. FIG. 4B shows themagnetic sensor 105D in relation to the lines 120D and 120E.

The apparatus 100 also includes a fluidic channel 115 (also referred toherein as a nanochannel) that is adjacent to the magnetic sensor array110. As its name suggests, the fluidic channel 115 is configured to holdfluids (e.g., liquids, gases, plasmas) when the apparatus 100 is in use.The fluidic channel 115 may by open (e.g., if its shape is rectangular,it may have three sides; if its shape is curved, it may have a shapethat is a portion of a cylinder; etc.) or closed (e.g., if its shape isrectangular, it may have four sides; if its shape is curved, it may becylindrical; etc.). The shape of the fluidic channel 115 may be regularor irregular. The fluidic channel 115 may be coupled to a pump thatforces fluids into the fluidic channel 115. Alternatively, the fluidicchannel 115 may be passive (e.g., it merely receives fluids but is notcoupled to a device that injects or removes fluids).

The fluidic channel 115 has a wall 117 that is adjacent to the magneticsensor array 110. The wall 117 may be referred to as a proximal wall.The wall 117 may be substantially vertical as illustrated in FIG. 4B.Alternatively, the wall 117 may be sloped at least in part (e.g., someor all of the interior of the fluidic channel 115 may be curved (e.g.,in the shape of a portion or all of a cylinder)). In general, thefluidic channel 115 and wall 117 may have any shapes that allow themagnetic sensors 105 to detect the presence of magnetic particles on theother side of the wall 117, within the fluidic channel 115.

When the apparatus 100 is in use, the magnetic sensors 105 are able todetect, through the wall 117, magnetic nanoparticles (MNPs) that are inthe fluidic channel 115. Thus, the wall 117 has properties andcharacteristics that protect the magnetic sensors 105 from whateverfluid is in the fluidic channel 115 while still allowing the magneticsensors 105 to detect MNPs that are within the fluidic channel 115. Forexample, the material of the wall 117 (and potentially of the rest ofthe fluidic channel 115) may be or comprise an insulator. For example,in some embodiments, a surface of the wall 117 comprises polypropylene,gold, glass, and/or silicon. In addition, the thickness of the wall 117may be selected so that the magnetic sensors 105 can detect MNPs withinthe fluidic channel 115. In some embodiments, the wall 117 isapproximately 2 nm to approximately 20 nm thick.

In some embodiments, the wall 117 has a structure (or multiplestructures) configured to anchor molecules to be sensed (e.g., nucleicacid or molecules of a nucleic acid polymerase) to the wall 117. Forexample, the structure (or structures) of the wall 117 may include acavity or a ridge.

To simplify the explanation, FIGS. 4A and 4B illustrate an exemplaryapparatus 100 with a single fluidic channel 115 and only four magneticsensors 105A, 105B, 105C, 105D in the magnetic sensor array 110. It isto be appreciated that the apparatus 100 may have many more magneticsensors 105 in the magnetic sensor array 110, and it may have eitheradditional fluidic channels 115 or a more intricate single fluidicchannel 115 (e.g., with a different shape or with interconnectedchannels). In general, any configuration of magnetic sensors 105 andfluidic channel(s) 115 that allows the magnetic sensors 105 to detectMNPs in the fluidic channel(s) 115 may be used.

As illustrated in FIG. 4C, the apparatus 100 includes sensing circuitry130 coupled to the magnetic sensor array 110 via the lines 120. In someembodiments, in operation, the sensing circuitry 130 applies a currentto the lines 120 to detect a characteristic of at least one of theplurality of magnetic sensors 105 in the magnetic sensor array 110,where the characteristic indicates a presence or an absence of amagnetically-labeled nucleotide precursor in the fluidic channel 115.For example, in some embodiments, the characteristic is a magnetic fieldor a resistance, or a change in magnetic field or a change inresistance, current, and/or voltage drop. In some embodiments, thecharacteristic is a magnetic noise, a noise level, a noise jitter,and/or a noise variance.

As an example of an apparatus 100 with a larger number of magneticsensors 105 in the magnetic sensor array 110, FIGS. 5A, 5B, 5C, and 5Dillustrate portions of an exemplary apparatus 100 that includes severalchannels, one or more of which may be a separate fluidic channel 115 inaccordance with some embodiments, or the aggregation of which may beconsidered a single fluidic channel 115. In the embodiment of theapparatus 100 shown in FIGS. 5A, 5B, 5C, and 5D, the plurality ofmagnetic sensors 105 of the magnetic sensor array 110 is arranged in arectangular grid pattern. Each of the lines 120 identifies a row or acolumn of the magnetic sensor array 110. It is to be understood thatFIGS. 5A, 5B, 5C, and 5D show only a portion of the apparatus 100 toavoid obscuring the parts of the apparatus 100 being discussed. It is tobe understood that the various illustrated components (e.g., lines 120,magnetic sensors 105, fluidic channels 115, etc.) might not be visiblein a physical instantiation of the apparatus 100 (e.g., some or all maybe covered by protective material, such as an insulator).

FIG. 5A is a perspective view of the exemplary apparatus 100 inaccordance with some embodiments. The apparatus 100 includes nine lines120, labeled as 120A, 120B, 120C, 120D, 120E, 120F, 120G, 120H, and120I. It also includes five fluidic channels, labeled as 115A, 115B,115C, 115D, and 115E. As explained above, the fluidic channels 115A,115B, 115C, 115D, and 115E may be considered to be separate fluidicchannels 115 or a single fluidic channel 115. The apparatus 100 also hasa bottom surface 119.

FIG. 5B is a top view of the exemplary apparatus 100 from FIG. 5A. Thelines 120G, 120H, and 120I, which are not visible from the top view, areshown using dashed lines to indicate their locations. The lines120A-120F are shown in solid lines but, as explained above, the lines120A-120F might also not be visible in the top view (e.g., they may becovered by protective material, such as an insulator).

FIG. 5C is a cross-sectional view of the apparatus 100 along the linelabeled “5C” in FIG. 5A. As shown, each of the lines 120A, 120B, 120C,120D, 120E, and 120F is in contact with the top of one of the magneticsensors 105 along the cross-section (namely, line 120A is in contactwith magnetic sensor 105A, line 120B is in contact with magnetic sensor105B, line 120C is in contact with magnetic sensor 105C, line 120D is incontact with magnetic sensor 105D, line 120E is in contact with magneticsensor 105E, and line 120F is in contact with magnetic sensor 105F). Theline 120H is in contact with the bottom of each of the magnetic sensors105A, 105B, 105C, 105D, 105E, and 105F. It is to be appreciated thatalthough FIGS. 5A-5D illustrate the lines 120 in contact with themagnetic sensors 105, the lines 120 may, in general, be coupled to themagnetic sensors 105 (i.e., they may be directly connected, or there maybe intervening components disposed between the lines 120 and themagnetic sensors 105).

The magnetic sensors 105A and 105B are separated by the fluidic channel115A (unlabeled in FIG. 5C but shown in FIG. 5A). Similarly, themagnetic sensors 105B and 105C are separated by the fluidic channel115B, the magnetic sensors 105C and 105D are separated by the fluidicchannel 115C, the magnetic sensors 105D and 105E are separated by thefluidic channel 115D, and the magnetic sensors 105E and 105F areseparated by the fluidic channel 115E. As discussed further below,either or both of the vertical walls of each fluidic channel 115 may bethe wall 117.

In some embodiments, each magnetic sensor 105 is assigned to a singlefluidic channel 115. For example, in the exemplary device illustrated inFIGS. 5A-5D, the magnetic sensors 105 coupled to the line 120A may beconfigured to sense MNPs in the fluidic channel 115A, the magneticsensors 105 coupled to the line 120B may be configured to sense MNPs inthe fluidic channel 115B, the magnetic sensors 105 coupled to the line120C may be configured to sense MNPs in the fluidic channel 115C, themagnetic sensors 105 coupled to the line 120D may be configured to senseMNPs in the fluidic channel 115D, and the magnetic sensors 105 coupledto the line 120E may be configured to sense MNPs in the fluidic channel115E.

In the exemplary embodiment illustrated in FIGS. 5A-5C, there are morecolumns of magnetic sensors 105 than there are fluidic channels 115(i.e., in the exemplary embodiment shown, there are six columnscorresponding to lines 120A-120F and only five fluidic channels115A-115E). In such embodiments, each vertical wall of one fluidicchannel 115 may be the wall 117. In other words, a single fluidicchannel 115 may be sensed by twice as many magnetic sensors 105 as eachof the other fluidic channels 115. For example, in the exemplaryembodiment of FIGS. 5A-5D, any of the fluidic channels 115 may be sensedby two columns of magnetic sensors 105. For example, the fluidic channel115B may be sensed by the magnetic sensors 105 coupled to both lines120B and 120C. In this example, the magnetic sensors 105 coupled to theline 120A would be assigned to sense the contents of the fluidic channel115A 120A, the magnetic sensors 105 coupled to the line 120D would beassigned to sense the contents of the fluidic channel 115C, the magneticsensors 105 coupled to the line 120E would be assigned to sense thecontents of the fluidic channel 115D, and the magnetic sensors 105coupled to the line 120F would be assigned to sense the contents of thefluidic channel 115E.

FIG. 5D is a cross-sectional view of the apparatus 100 along the linelabeled “5D” in FIG. 5A. As shown, the line 120E is in contact with thetop of each of the sensors 105G, 105E, and 105H along the cross-section.Each of the lines 120G, 120H, and 120I is in contact with the bottom ofone of the magnetic sensors 105 along the cross-section (namely, line120G is in contact with magnetic sensor 105G, line 120H is in contactwith magnetic sensor 105E, and line 120I is in contact with magneticsensor 105H). As explained above, the lines 120 shown in FIG. 5D neednot be in direct contact with the magnetic sensors 105; instead, theymay be connected through intervening components.

In some embodiments (see, e.g., FIGS. 5E, 5F), the apparatus 100includes a plurality of selector elements 111, each of which is coupledto a respective one of the magnetic sensors 105, where each of theselector elements 111 exhibits thresholding behavior such that forvoltages above a given value (i.e., V_(th)) the selector element 111 hashigh conductivity, and below that voltage the conductivity of theselector element 111 is effectively zero. The selector elements 111 maycomprise, for example, transistors, diodes, etc. As will be appreciatedby those having ordinary skill in the art, different schemes ofaddressing (selecting) the magnetic sensors 105 (individually or ingroups) can be used that ensure only the voltage dropped across theintended magnetic sensor(s) 105 is above V_(th). Accordingly, selectorelements 111 may be used reduce the chances of “sneak” currents thatcould transmit through neighboring elements and degrade the performanceof the apparatus 100.

FIG. 5E illustrates an exemplary magnetic sensor 105 selection approachin accordance with some embodiments. In the exemplary embodiment shownin FIG. 5E, a respective selector element 111 (e.g., shown as a CMOStransistor) is coupled in series with the magnetic sensor 105. In thisexemplary embodiment, three lines 120A, 120B, and 120C allow acharacteristic of the magnetic sensor 105 to be sensed. Conceptually,the line 120A may be considered to be a read-out line, the line 120C maybe considered to be a control line, and the line 120B may be consideredto be either or both a read-out line and a control line. For more detailon configurations such as the exemplary one shown in FIG. 5E, see B. N.Engel, J. Åkerman, B. Butcher, R. W. Dave, M. DeHerrera, M. Durlam, G.Grynkewich, J. Janesky, S. V. Pietambaram, N. D. Rizzo, J. M. Slaughter,K. Smith, J. J. Sun, and S. Tehrani, “A 4-Mb Toggle MRAM Based on aNovel Bit and Switching Method,” IEEE Transactions on Magnetics, Vol.41, 132 (2005).

FIG. 5F illustrates another exemplary magnetic sensor 105 selectionapproach in accordance with some embodiments. In the exemplaryembodiment shown in FIG. 5F, a selector element 111 (e.g., a diode or asimilar thresholding element, as is known in the art, such assemiconductor diodes, operational transconductance amplifiers (OTAs),vanadium oxide layers, capacitive threshold-logic gates, etc.) isdeposited “in-stack” together with the magnetic films of the magneticsensors 105 and then placed into a cross-point architecture. AlthoughFIG. 5F shows the in-stack selector elements 111 over the magneticsensors 105, it is to be understood that the order of the in-stackselector elements 111 and the magnetic sensors 105 may be reversed.Respective selector devices (e.g., CMOS transistors) may be used to turnon the individual lines 120A, 120B to address/access individual magneticsensors 105 in the apparatus 100. The use of CMOS select transistors maybe simple due to the prevalence of foundries available to fabricate thefront end (i.e., all the nanofabrication to build the CMOS transistorsand underlying circuitry), but the types of currents used for operationmay use a cross-point design to eventually reach the densities desired.Additional details on configurations suitable to select magnetic sensors105 (e.g., in cross-point arrays) may be found in C. Chappert, A. Fert,and F. N. Van Daul, “The emergence of spin electronics in data storage,”Nature Materials, Vol. 6, 813 (2007) and in J. Woo et al.,“Selector-less RRAM with non-linearity of device for cross-point arrayapplications,” Microelectronic Engineering 109 (2013) 360-363.

In some embodiments, the apparatus 100 is fabricated usingphotolithographic processes and thin film deposition. FIG. 6 illustratesa method 150 of manufacturing the apparatus 100, and FIG. 7 illustratesthe results of each step of the fabrication process 150 with a finalpanel showing polymerase bound to the wall 117 proximate to a magneticsensor 105 in accordance with some embodiments (e.g., when the apparatus100 is used for nucleic acid sequencing). At 152, the method begins. At154, at least one line 120 is fabricated on a substrate, for example, bydepositing one or more metal layers, using, for example,photolithography to pattern an array of lines and spaces in a polymerlayer applied on top of the metal layers, using that polymer as a maskfor etching the metal layers into an array of lines, depositing aninsulating dielectric material, stripping the polymer and dielectricover the lines, and performing chemical mechanical polishing toplanarize the surface. At 156, the magnetic sensor array 110 isfabricated on the at least one line 120. Each magnetic sensor 105 of themagnetic sensor array 110 has a bottom portion 108 and a top portion109. (See FIG. 1.) The bottom portion 108 is coupled to the at least oneline 120. In some embodiments, the bottom portion 108 of each magneticsensor 105 is in contact with the at least one line 120.

At 158, dielectric material is deposited between the magnetic sensors105 of the magnetic sensor array 110. At 160, additional lines 120 arefabricated. Each of these additional lines 120 is coupled to the topportion 109 of at least one magnetic sensor 105 in the magnetic sensorarray 110. In some embodiments, the top portion 109 of each magneticsensor 105 is in contact with an line 120. In some embodiments, thebottom portion 108 of a magnetic sensor 105 is in contact with a firstline 120A, and the top portion 109 of the magnetic sensor 105 is incontact with a second line 120B. At 162, a portion of the dielectricmaterial adjacent to the magnetic sensors 105 is removed (e.g., bymilling, etching, or any other suitable removal process) to create thefluidic channel 115. At 164, the process 150 ends.

As described herein, the exemplary apparatus 100 shown in FIG. 7 can beused with methods using SBS protocols that use magnetically-labelednucleotide precursors. SBS involves binding of primer-hybridizedtemplate DNA, incorporation of a deoxynucleoside triphosphate (dNTP),and detection of incorporated dNTP. The apparatus 100 (as shown in FIGS.4A-4C and FIGS. 5A-5E) can be used to expose the magnetic sensors 105 tosequencing reagents in the fluidic channel(s) 115 while protecting themagnetic sensors 105 using, for example, an electrically-insulatingmaterial. DNA synthesis may be performed using polymerase moleculesplaced in the proximity of the magnetic sensors 105, which detect MNPs(e.g., as shown in the final panel of FIG. 7).

In particular, either molecules of polymerase or fragments ofsingle-strand nucleic acid may be attached to the side wall(s) 117 ofthe fluidic channel(s) 115 in the proximity of one or more of themagnetic sensors 105. Sequencing can then be performed by adding, to thefluidic channel(s) 115, a nucleic acid template (having a primer bindingsite and an extendable primer) and magnetically-labeled nucleotideprecursors (each type of nucleotide precursor labeled by adistinguishable MNP), and sequencing the nucleic acid template by usingthe lines 120 to detect a characteristic of the magnetic sensors 105that indicates which of the magnetically-labeled nucleotide precursorshas been incorporated into the extendable primer. For DNA sequencingspecifically, because adenine (A) pairs only with thymine (T) andcytosine (C) pairs only with guanine (G), detection of the MNPs enablesthe determination of which of the magnetically-labeled nucleotideprecursors has been incorporated. Specifically, if the MNP labeling A isdetected, the recorded base is T (and vice versa), and if the MNPlabeling C is detected, the recorded base is G (and vice versa).

Some methods of using embodiments of the apparatus 100 described aboverely on the use of molecules that are magnetically-labeled by magneticnanoparticles, such as, for example, a magnetic molecule, asuperparamagnetic nanoparticle, or a ferromagnetic particle. Thesemagnetic nanoparticles may be cleavable. For example, for nucleic-acidsequencing applications, nucleotide precursors to be sequenced maycomprise cleavable MNPs.

There are a number of ways to attach and (if applicable) cleave theMNPs. For example, the MNPs may be attached to a base or a molecule tobe detected, in which case they may be cleaved chemically. As anotherexample, the MNPs may be attached to a phosphate, in which case they maybe cleaved by, for example, polymerase or, if attached via a linker, bycleaving the linker.

In some embodiments for nucleic acid sequencing, the magnetic label islinked to the nitrogenous base (A, C, T, G, or a derivative) of thenucleotide precursor. After incorporation of the nucleotide precursorand the detection by the apparatus 100 (i.e., using the magnetic sensorarray 110), the magnetic label may be cleaved from the incorporatednucleotide.

In some embodiments, the magnetic label is attached via a cleavablelinker. Cleavable linkers are known in the art and have been described,e.g., in U.S. Pat. Nos. 7,057,026, 7,414,116 and continuations andimprovements thereof. In some embodiments, the magnetic label isattached to the 5-position in pyrimidines or the 7-position in purinesvia a linker comprising an allyl or azido group. In other embodiments,the linker comprises a disulfide, indole and/or a Sieber group. Thelinker may further contain one or more substituents selected from alkyl(C₁₋₆) or alkoxy (C₁₋₆), nitro, cyano, fluoro groups or groups withsimilar properties. Briefly, the linker can be cleaved by water-solublephosphines or phosphine-based transition metal-containing catalysts.Other linkers and linker cleavage mechanisms are known in the art. Forexample, linkers comprising trityl groups, p-alkoxybenzyl ester groups,p-alkoxybenzyl amide groups, tert-butyloxycarbonyl (Boc) groups. and theacetal-based groups can be cleaved under acidic conditions by aproton-releasing cleavage agent such as an acid. A thioacetal or othersulfur-containing linker can be cleaved using a thiophilic metals, suchas nickel, silver or mercury. The cleavage protecting groups can also beconsidered for the preparation of suitable linker molecules. Ester- anddisulfide containing linkers can be cleaved under reductive conditions.Linkers containing triisopropyl silane (TIPS) or t-butyldimethyl silane(TBDMS) can be cleaved in the presence of F ions. Photocleavable linkerscleaved by a wavelength that does not affect other components of thereaction mixture include linkers comprising o-nitrobenzyl groups.Linkers comprising benzyloxycarbonyl groups can be cleaved by Pd-basedcatalysts.

In some embodiments, the nucleotide precursor comprises a label attachedto a polyphosphate moiety as described in, e.g., U.S. Pat. Nos.7,405,281 and 8,058,031. Briefly, the nucleotide precursor comprises anucleoside moiety and a chain of 3 or more phosphate groups where one ormore of the oxygen atoms are optionally substituted, e.g., with S. Thelabel may be attached to the α, β, γ or higher phosphate group (ifpresent) directly or via a linker. In some embodiments, the label isattached to a phosphate group via a non-covalent linker as described,e.g., in U.S. Pat. No. 8,252,910. In some embodiments, the linker is ahydrocarbon selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl, and substituted or unsubstitutedheterocycloalkyl; see, e.g., U.S. Pat. No. 8,367,813. The linker mayalso comprise a nucleic acid strand; see, e.g., U.S. Pat. No. 9,464,107.

In embodiments in which the magnetic label is linked to a phosphategroup, the nucleotide precursor is incorporated into the nascent chainby the nucleic acid polymerase, which also cleaves and releases thedetectable magnetic label. In some embodiments, the magnetic label isremoved by cleaving the linker, e.g., as described in U.S. Pat. No.9,587,275.

In some embodiments, the nucleotide precursors are non-extendable“terminator” nucleotides, i.e., the nucleotides that have a 3′-endblocked from addition of the next nucleotide by a blocking “terminator”group. The blocking groups are reversible terminators that can beremoved in order to continue the strand synthesis process as describedherein. Attaching removable blocking groups to nucleotide precursors isknown in the art. See, e.g., U.S. Pat. Nos. 7,541,444, 8,071,739 andcontinuations and improvements thereof. Briefly, the blocking group maycomprise an allyl group that can be cleaved by reacting in aqueoussolution with a metal-allyl complex in the presence of phosphine ornitrogen-phosphine ligands.

FIGS. 8A through 8C illustrate an embodiment of a cross-point arrayarchitecture 300 that may be included in the apparatus 100 in accordancewith some embodiments. For illustration, the magnetic sensors 105illustrated in FIGS. 8A through 8C comprise MTJ elements 308, but it isto be appreciated that other types of sensors (e.g., spin valve devices)may be used. It is to be appreciated that although various particular MRsensor types were described above, the description is not intended toexclude other MR sensor types.

Referring to FIG. 8A, the cross-point array architecture 300 includestop wires 318 and bottom wires 320 (each of which is an line 120). Asshown in the exemplary embodiment of FIG. 8A, the top wires 318 areoriented at substantially 90° angles to the bottom wires 320 as shown.An example MTJ element 308 is situated between a crossing of the array.The example MTJ element 308 includes two or more FM layers separated byone or more non-magnetic layers 316 (e.g., MgO). As shown, one of the FMlayers is a free layer 310 that will rotate in the presence of amagnetic field, and another of the FM layers is a pinned (or fixed)layer 314 that may be a single FM coupled to an AFM layer 312.Alternatively, a compound structure called a synthetic antiferromagnet(SAF) may be used. The SAF includes two FM layers separated by amagnetic coupling layer (e.g., ruthenium), with one of the two FM layerscoupled to an AFM layer. It is to be understood that although theexample layer arrangement of MTJ element 308 shows a general structurewith layers over or under other layers, intervening layers not shown canbe inserted.

To illustrate some of the features of the cross-point array architecture300, FIG. 8B shows a cross-section of the cross-point array architecture300 along the top wire 318 direction (indicated in FIG. 8A by thedash-dot line labeled “8B”), and FIG. 8C shows a cross-section of thecross-point array architecture 300 along the bottom wire 320 direction(indicated in FIG. 8A by the dashed line labeled “8C”). As shown, thesides of the MTJ elements 308 (which may be the magnetic sensors 105)are encapsulated by insulating material 336. Optionally, as shown inFIG. 8B, a hard bias magnetic material 338 may also be deposited betweenthe MTJ elements 308. If present, the hard bias magnetic material 338may be magnetized to point in a direction parallel to the direction ofthe top wire(s) 318. In embodiments including hard bias magneticmaterial 338, a thin layer of insulator 340 is also deposited on top ofthe hard bias magnetic material 338 to electrically insulate it from thetop wire(s) 318.

In some embodiments, the orientation of the free layer 310 moment is atan angle approximately 90° from the pinned layer 314 moment (as shown inthe left side panel of FIG. 9A, discussed further below), which can beachieved using one or more strategies. The first is by using a hard biasfield in which the hard bias magnetized along the direction of the topmagnet also applies a magnetic field across the MTJ elements 308 in thedirection of the top wire 318. Because the pinned layer 314 is fixedusing an AFM layer 312, its moment can be chosen to be perpendicular tothe hard bias field, but the free layer 310 will rotate to be roughlyparallel to the hard bias field.

A second way to achieve this orientation configuration is to pattern theMTJ elements 308 into rectangles or ellipses, where the long axis of theMTJ elements 308 is along the direction of the top wire(s) 318. Throughthe aspect ratio of these shapes, a shape anisotropy energy can betuned, which creates an axis along the length of the top wire(s) 318along which the free layer 310 magnetization will preferentially pointin the absence of an external magnetic field.

A third way to achieve this orientation configuration is by etching theFM layers 310, 314 along an axis to induce texturing (see, e.g., U.S.Pat. No. 7,382,586), which can also create uniaxial anisotropy so thatthe free layer 310 moment will point along the length of the top wire(s)318.

A fourth way to achieve this orientation configuration is to useperpendicular magnetic anisotropy to pull the free layer 310 out ofplane while keeping the pinned layer 314 in the plane of the film, orvice versa. The anisotropy of the free layer 310 is kept small enoughthat a small in-plane field can rotate the free layer 310 in plane,which is qualitatively similar to the other methods described above.There are other methods to achieve a 90° orientation between the freeand pinned layer moments in addition to those mentioned here, andachieving this orientation is not limited to these options.

Referring to FIG. 8C, the cross section shows the fluidic channels 115(e.g., nanofluidic or microfluidic channels), which may be, for example,trenches etched in an insulator. As shown, a small amount of insulator322 is left on the sidewalls of the magnetic sensors 105 (illustrated asMTJ elements 308) so that the MNPs do not electrically interact with themagnetic sensors 105. The portion of the insulator exposed to (andforming) the fluidic channel 115 may form the wall 117 to whichpolymerase molecules or molecules to be detected (e.g., nucleic acidsamples) may be attached for sequencing.

Detection of MNPs can be performed in a variety of ways. To achievehigh-throughput sequencing relying on each magnetic sensor 105 beingcapable of detecting a single MNP (e.g., a nanoparticle), the MNPsshould be small, ideally comparable to the size of an individualmagnetic sensor 105. This can be achieved with a variety of MNPs thatcan be readily synthesized as is known in the art. For example, the MNPsmay be nanoparticles with high magnetic anisotropy. Examples ofnanoparticles with high magnetic anisotropy include, but are not limitedto, Fe₃O₄, FePt, FePd, and CoPt. To facilitate chemical binding tonucleotides, the particles may be synthesized and coated with SiO₂. See,e.g., M. Aslam, L. Fu, S. Li, and V. P. Dravid, “Silica encapsulationand magnetic properties of FePt nanoparticles,” Journal of Colloid andInterface Science, Volume 290, Issue 2, 15 Oct. 2005, pp. 444-449.

Because MNPs of this size have permanent magnetic moments, thedirections of which fluctuate randomly on very short time scales, someembodiments rely on sensitive sensing schemes that detect fluctuationsin magnetic field caused by the presence of the MNPs.

In some embodiments, the sensing circuitry 130 detects deviations orfluctuations in the magnetic environment of some or all of the magneticsensors 105 in the magnetic sensor array 110. For example, a magneticsensor 105 of the MR type in the absence of a MNP should have relativelysmall noise above a certain frequency as compared to a magnetic sensor105 in the presence of a MNP, because the field fluctuations from theMNP will cause fluctuations of the moment of the sensing ferromagnet.These fluctuations can be measured using heterodyne detection (e.g., bymeasuring noise power density) or by directly measuring the voltage ofthe magnetic sensor 105 and evaluated using a comparator circuit tocompare to a dummy sensor element that does not sense the fluidicchannel 115. One advantage of the array design embodiment illustrated inFIG. 2A is that multiple magnetic sensors 105 (e.g., nominally to theleft and right of a MNP) can be used in post-processing of data toimprove the accuracy of MNP detection.

In applications in which the apparatus 100 is used to detect biologicmolecules (e.g., for nucleic acid sequencing applications), it may bedifficult to orient the moments of each of the MNPs (e.g.,nanoparticles) in the same direction, as the position of each label withrespect to a magnetic sensor 105 as well as the axis of the label'smagnetic moment can vary. Moreover, to achieve high densities ofmagnetic sensors 105 in the magnetic sensor array 110, the MNPs may needto be on the order of tens of nanometers, in which case the MNPs arelikely to be superparamagnetic, meaning that they maintain a measurablemoment without a defined axis for the moment to point (i.e., themagnetic field acting on a magnetic sensor 105 would fluctuate in timein its direction). These challenges can increase the difficulty ofaccurate detection. To mitigate these challenges, an external magneticfield may be used (e.g., to align the moments of the MNPs insubstantially the same direction) as well as to address the magneticsensors 105.

In some embodiments, target molecules to be detected (e.g., nucleic acidstrands to be sequenced) are attached to the walls 117 of the fluidicchannels 115 as shown in the left panel of FIG. 9A and may havepolymerase introduced at this point. Individual bases with attached MNPsmay then be introduced into the fluidic channels 115. The appropriate(complementary) base pair (i.e., for DNA sequencing, cytosine (C) withguanine (G) or adenine (A) with thymine (T)) will then be incorporatedand can be detected. Assuming this process is done one base pair at atime, sub-panel 402 (left) of FIG. 9A illustrates a detection methodaccording to an embodiment in which the presence or absence of the MNP,and therefore the base, can be determined using the various deviceembodiments of, for example, FIGS. 4A-4C, 5A-5D, and 8A-8C. As shown insub-panel 402, polymerase 410 is bound to the wall 117 and is used tocapture induced DNA bases for detection. The MNPs used can be eithersuperparamagnetic or weakly magnetic, as it is beneficial that they donot require a large magnetic field to align their moments to themagnetic field.

Sequencing occurs by applying a magnetic field (Happ) across the MTJelement 308 (an example of the magnetic sensor 105). The magnetic fieldmay be applied using an electromagnet, e.g., by placing the pole pieceson either side of the apparatus 100), a distributed coil, a solenoidoriented perpendicular to the fluidic channel 115, etc. to generate themagnetic field in the direction of the pinned layer's moment 406. Themeans for generating the magnetic field may be mounted, for example, onthe bottom surface 119 of the apparatus 100. As another example, themeans for generating a magnetic field may be included in a system thatincludes the apparatus 100. It is to be understood that other suitablemeans of generating the magnetic field, such as, for example, by usingpermanent magnets or super-conducting magnets, are possible, arespecifically contemplated herein, and are not excluded.

The applied magnetic field can achieve at least two objectives: (1) italigns the moments of all the MNPs in a common direction so that themeasured signals due to the presence of a MNP are similar, and (2) itrotates the free layer's moment 408 toward (or away from, depending onthe field orientation) the pinned layer's moment 406 and thus changesthe resistance of the magnetic sensor 105 from its equilibriumresistance.

The right-hand portion of FIG. 9A illustrates the pinned layer 314(labeled “fixed”) and free layer 310 as if viewing sub-panel 402 fromabove. The pinned layer 314 and free layer 310 are drawn offset fromeach other to illustrate their moments. The dashed line 424 shown in thefree layer 310 is the equilibrium direction of the free layer 310'smoment. In the absence of a MNP near the MTJ element 308 (or, moregenerally, the magnetic sensor 105), illustrated as case 418 (top) onthe right-hand side of FIG. 9A, the magnetic field can rotate themagnetic moment 408 of the free layer 310 into the direction of themagnetic moment 406 of the pinned layer 314 (depending on the details ofthe MTJ element 308/magnetic sensor 105 design). In the presence of aMNP near the MTJ element 308 (or, more generally, the magnetic sensor105), illustrated as case 420 (bottom) on the right-hand side of FIG.9A, fringing fields (Hparticle) will be created. These fringing fieldswill be in the same direction as the applied field and, therefore, canadd significantly to the applied field locally near the magnetic sensor105 (shown as a MTJ element 308). The magnetic moment 408 of the freelayer 310 will then rotate more substantially from its equilibriumposition (dashed line 424), as shown in case 420. Therefore, byconnecting the magnetic sensors 105 to detection electronics thatmeasure the resistance of the magnetic sensors 105 (or a proxy for theresistance, such as, for example, the voltage across the magneticsensors 105 for a given current), the presence or absence of a MNP canbe detected. The detection can be accomplished by either measuring theabsolute resistance of each magnetic sensor 105 (e.g., each MTJ element308) or by comparing the resistances to a reference cell or bit (e.g., amagnetic sensor 105 that is completely encapsulated such that it is notexposed to or affected by the field from a MNP).

FIG. 9B illustrates another embodiment in which the magnetic moments 408and 406 of, respectively, the free layer 310 and pinned layer 314 arereversed in arrangement relative to FIG. 9A. The dashed line 434 shownin the free layer 310 is the equilibrium direction of the free layer310's moment. As FIG. 9B illustrates, if the applied field Happ is inthe direction along the fluidic channel 115, the fringing fieldHparticle will be in an opposite direction to the applied field Happ.Thus, in the absence of a MNP near the MTJ element 308 (or, moregenerally, the magnetic sensor 105), illustrated as case 440 (top) onthe right-hand side of FIG. 9B, the magnetic field can rotate themagnetic moment 408 of the free layer 310 into the direction of themagnetic moment 406 of the pinned layer 314 (depending on the details ofthe MTJ element 308/magnetic sensor 105 design). In the presence of aMNP, however, the magnetic moments 408 and 406 will be closer to a90-degree alignment as shown in the bottom portion of the right-handside of FIG. 9B (case 450).

Using the detection methodology described above for DNA sequencing, forexample, detecting which of four magnetically-labeled nucleotideprecursors has been incorporated into the extendable primer can beaccomplished in four chemistry steps, one for each of the four bases. Ineach step, a binary (yes/no, 1/0, etc.) determination may be made as towhether the magnetically-labeled nucleotide precursor being tested hasbeen incorporated.

In another embodiment, instead of using a binary method with fourchemistry steps for each read, either three or four different MNPs canbe used as the magnetic labels. Each of the different MNPs has adifferent saturation magnetization so that it generates a magnetic fieldof a magnitude that distinguishes it from the magnetic fields generatedby all other MNPs being used as magnetic labels. For example, in a DNAsequencing application, A can be labeled using MNP1, T using MNP2, Cusing MNP3, and G either using MNP4 or left unlabeled, where thesaturation magnetizations of MNP1, MNP2, MNP3, and (if used) MNP4 areall different enough that the three or four types of particles can bedistinguished. Then all four bases can be introduced into the fluidicchannel 115 at the same time, and the magnitude of the resistancedetected via the magnetic sensors 105 can be used to identify which MNP(and therefore base) is incorporated in the vicinity of each magneticsensor 105. For example, assume the resistance of a magnetic sensor 105is expected to vary in accordance with the following table in thepresence of four different MNPs:

Magnetic Expected minimum Expected maximum Base nanoparticle identityresistance resistance labeled MNP1 R1 <R2 A MNP2 R2 <R3 T MNP3 R3 <R4 CMNP4 R4 <R5 GIn some embodiments, the expected resistance ranges are nonoverlapping.Thus, assume that R1<R2<R3<R4<R5. If the detected resistance of amagnetic sensor 105 is greater than R2 but less then R3, it can bedetermined that thymine (T) was incorporated, and that the base of theDNA strand being sequenced is adenine (A).

It is to be understood that it is not necessary to use four MNPs. Insome embodiments, one of the bases is unlabeled. Using the exampleabove, and assuming that guanine (G) is left unlabeled, the tablebecomes:

Magnetic Expected minimum Expected maximum Base nanoparticle identityresistance resistance labeled MNP1 R1 <R2 A MNP2 R2 <R3 T MNP3 R3 <R4 CMNP4 Reference Reference G (optionally (optionally minus tolerance) plustolerance)Relative to the example above, the incorporation of A, T, and C is doneas previously described, but the incorporation of G is detected bydetecting that the resistance of a magnetic sensor 105 is approximatelya reference value (i.e., whatever the expected value of the resistanceis in the absence of any MNP). Optionally, a tolerance can be used tocreate the detection range for the unlabeled base to account forvariations in the expected resistance of a magnetic sensor 105 that isnot in the presence of any MNP.

After some or all sensors have been addressed and read, the magneticfield can be turned off and the MNPs may be cleaved from theincorporated magnetically-labeled nucleotide precursor using, forexample, enzymatic or chemical cleavage, as is known in the art. Theprocess can then be repeated for the next unpaired base in the strandbeing sequenced. This embodiment allows for a single chemistry step perbase read.

In some embodiments, instead of applying an external magnetic field anddetecting the resistances (or a proxy for resistance, such as voltage ata particular current) of the magnetic sensors 105 to detect the presenceor absence of a MNP, the magnetic noise of the magnetic sensors 105 isdetected (e.g., estimated, measured, etc.) without applying an externalmagnetic field. Specifically, as described below, fluctuations in themagnetic noise may be detected and used to determine whether a MNP ispresent.

A magnetic sensor 105 has an intrinsic magnetic noise because themagnetic moments of the materials in the magnetic sensor 105 fluctuateabout their equilibrium positions. Magnetic noise occurs due to thermalnoise that causes the moment of a ferromagnet to undergo smallfluctuations in direction over short time periods. This fluctuationtranslates to measurable noise signals in a MR device, because theseeffects cause fluctuations in the device resistance (or measured voltagefor a given current). In the frequency domain, these fluctuations arecalled 1/f (where f is frequency) noise because the magnitude of thenoise is proportional to 1/f. The characteristics (e.g., variance,amplitude, etc.) of the intrinsic magnetic noise can be determined inthe absence of any magnetic particle near the magnetic sensor 105.Changes to the characteristics of the magnetic noise can indicate thepresence of a MNP near the magnetic sensor 105.

Referring again to FIGS. 8A-8C, when the MNPs used to label themagnetically-labeled nucleotide precursors are superparamagnetic, thenoise of a particular magnetic sensor 105 (illustrated as MTJ element308) will change when a MNP is nearby because the magnetic sensor 105will also be exposed to a locally-fluctuating magnetic field due to theMNP, which can change both the amplitude and the frequency response ofthe magnetic sensor 105's noise. By monitoring/detecting the amplitudeof the noise (e.g., at specific frequencies or over a frequency band),or another characteristic of the noise, such as its fluctuations, orchanges in the amplitude and/or another characteristic of the noise of aparticular magnetic sensor 105, the presence or absence of a MNP in thevicinity of that particular magnetic sensor 105 can be detected.

Particle detection can be accomplished in several different ways. As oneexample, the noise amplitude (e.g., at one or more frequencies or withinone or more frequency bands) can be measured using a super-heterodynecircuit 500, such as the exemplary embodiment shown in FIG. 10A. Asshown in FIG. 10A, a (typically small) bias current 502 (e.g., a DC biascurrent) is applied to a magnetic sensor 105 (which may be, for example,a MTJ element 308 or any other suitable magnetic sensor 105), and theresultant signal is filtered by a low pass filter 506 having a suitablecutoff frequency (e.g., a cutoff frequency below 100 MHz). The signal isthen amplified by an amplifier 510 (e.g., a RF amplifier), and a mixer512 multiplies the signal by a reference signal from a local referenceoscillator 508. The local reference oscillator 508 has a fixed frequencychosen to maximize the change in signal at that frequency when aparticular MNP is present. The frequency of the local referenceoscillator 508 may be different to detect different MNPs. The output ofthe mixer 512 is filtered by a second low pass filter 514 (which may besimilar or identical to the low pass filter 506) and amplified by asecond amplifier 516 (e.g., a RF amplifier). The signal is sent throughan envelope detector, shown in FIG. 10A as a diode detector 518. Theoutput 520 of the envelope detector (diode detector 518) is then sent todetection electronics that measure the voltage of the signal. Thisvoltage is proportional to the noise of the magnetic sensor 105.Therefore, changes in the noise level (e.g., an increase or decrease inthe voltage level (noise amplitude)) over time can indicate the presenceor absence of a MNP.

An alternative detection circuit 580, which enables detection offluctuations in the magnetic noise (sometimes referred to as “magnoise”), is illustrated in FIG. 10B. As shown in FIG. 10B, a biascurrent 502 (e.g., a DC bias current) is applied to a magnetic sensor105 (which may be, for example, a MTJ element 308 or any other suitablemagnetic sensor 105), and the resultant signal is amplified by a RFamplifier 510 and filtered by a filter 582 (e.g., a bandpass filter)having a suitable cutoff frequency selected to allow the mag noisejitter in the presence of a MNP to be distinguished from the mag noisejitter in the absence of a MNP (e.g., a band of frequencies ofapproximately 1 kHz to 100 MHz). The signal may then (optionally) beamplified by another amplifier 516 (e.g., a RF amplifier), and anenvelope detector, shown in FIG. 10B as a diode detector 518, provides aDC output 590. The DC output 590 is nonzero when a MNP is presentbecause the fluctuations in the mag noise will be higher in the presenceof a MNP than in the absence of a MNP. Therefore, changes in the DCoutput 590 over time can indicate the presence or absence of a MNP.

An alternative embodiment of a detection circuit 550 is shown in FIG.11. The circuit 550 allows the mag noise of the magnetic sensor 105 tobe measured directly. In the detection circuit 550, the AC response ofthe magnetic sensor 105's mag noise is tracked by a phase locked loop(PLL) 566. The circuit 550 includes many of the same elements as thedetection circuits 500 and 580 shown in FIGS. 10A and 10B, and thedescriptions of those elements are not repeated here.

In the exemplary embodiment of FIG. 11, the PLL 566 includes a signalgenerator 522, which generates a clean RF signal based on a tuning input524. The tuning input 524 comes from components 526 and 528 forming aloop filter with an error amplifier 532. The clean RF signal from thesignal generator 522 is combined (mixed) with the signal coming from theamplifier 510 at a mixer 512, and then filtered by a low pass filter 530of the PLL 566. The resultant error signal 534 of the PLL 566 is themagnetic noise of the magnetic sensor 105, the characteristics of whichdepend on (e.g., are influenced or changed by) the presence or absenceof a MNP. Thus, the error signal 534 can be used to detect the presenceor absence of a MNP.

Electrical detection for DNA sequencing as described in this disclosurehas several advantages over currently used technologies involvingoptical detection methods, with a primary advantage being thatelectrical detection is not limited in terms of scaling flow celldimensions in the same manner that optical detection is limited due tooptical imaging being diffraction limited. Magnetic detection is a formof electrical detection for sequencing that has advantages over commonlyproposed tunnel current detection schemes, because tunneling currentmethods rely on the measurement of extremely small currents (whichreduces SNR), and the tunnel junction elements to be exposed directly tothe sequencing chemistries, which could cause corrosion or otherdetrimental issues that degrade the accuracy of the sequencing process.By comparison, magnetic detection has much larger signals (and bettersignal-to-noise ratio (SNR)) and can be performed without magneticparticles labeling the bases being in direct contact with the sensorelements, thereby allowing sensor elements to be coated in a protectivelayer that would prevent interactions with the sequencing chemistries.

For the various embodiments of the disclosure discussed here, a MRsensor device as disclosed has at least the advantage that it takesadvantage of similar operating methodology of a magnetic recording readhead. It can be used in a simple binary detection process to detect thepresence of an introduced DNA base, or it can be used with multiple basereads at the same time (speeding up sequencing). It can also provideflexibility in the choice of MNPs used as tags for the DNA, as bothsuperparamagnetic and ferromagnetic particles are suitable.

One limitation of magnetic detection may be the signal to noise ratio ofthe magnetic sensors 105. At least one advantage of various embodimentsof the disclosure is that the magnetic field-based embodiments use anapplied magnetic field, which, generally speaking, reduces magneticnoise in the system. On the other hand, the noise-based detectionembodiments take advantage of magnetic noise by using it to detect thepresence or absence of magnetic particles (i.e., as a read mechanism).Another advantage is that, because some embodiments detect a singlevoltage (or resistance) for each sensor element, such a method is veryfast and allows for high data collection throughput, which is highlydesirable in a sequencing system.

Conditional language used herein, such as, among others, “can,” “could,”“might,” “may,” “e.g.,” and the like, unless specifically statedotherwise, or otherwise understood within the context as used, isgenerally intended to convey that certain embodiments include, whileother embodiments do not include, certain features, elements and/orsteps. Thus, such conditional language is not generally intended toimply that features, elements and/or steps are in any way required forone or more embodiments or that one or more embodiments necessarilyinclude logic for deciding, with or without other input or prompting,whether these features, elements and/or steps are included or are to beperformed in any particular embodiment. The terms “comprising,”“including,” “having,” and the like are synonymous and are usedinclusively, in an open-ended fashion, and do not exclude additionalelements, features, acts, operations, and so forth. Also, the term “or”is used in its inclusive sense (and not in its exclusive sense) so thatwhen used, for example, to connect a list of elements, the term “or”means one, some, or all of the elements in the list.

Disjunctive language such as the phrase “at least one of X, Y, Z,”unless specifically stated otherwise, is otherwise understood with thecontext as used in general to present that an item, term, etc., may beeither X, Y, or Z, or any combination thereof (e.g., X, Y, and/or Z).Thus, such disjunctive language is not generally intended to, and shouldnot, imply that certain embodiments require at least one of X, at leastone of Y, or at least one of Z to each be present.

Unless otherwise explicitly stated, articles such as “a” or “an” shouldgenerally be interpreted to include one or more described items.Accordingly, phrases such as “a device configured to” are intended toinclude one or more recited devices. Such one or more recited devicescan also be collectively configured to carry out the stated recitations.For example, “a processor configured to carry out recitations A, B andC” can include a first processor configured to carry out recitation Aworking in conjunction with a second processor configured to carry outrecitations B and C.

While the above detailed description has shown, described, and pointedout novel features as applied to various embodiments, it can beunderstood that various omissions, substitutions, and changes in theform and details of the devices or algorithms illustrated can be madewithout departing from the spirit of the disclosure. As can berecognized, certain embodiments described herein can be embodied withina form that does not provide all of the features and benefits set forthherein, as some features can be used or practiced separately fromothers. The scope of certain embodiments disclosed herein is indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

We claim:
 1. A sensing device, comprising: at least one fluidic channelconfigured to receive a plurality of molecules to be detected, whereinat least some of the plurality of molecules to be detected are coupledto respective magnetic nanoparticles (MNPs); a plurality ofmagnetoresistive (MR) sensors; an insulating material encapsulating theplurality of MR sensors and for providing a barrier between theplurality of MR sensors and contents of the at least one fluidicchannel; and detection circuitry coupled to each of the plurality of MRsensors, wherein: a surface of the insulating material within thefluidic channel provides a plurality of sites for binding the pluralityof molecules to be detected, the plurality of sites being located amongthe plurality of MR sensors, and the detection circuitry is configuredto detect a characteristic of a magnetic noise of each of the pluralityof MR sensors, wherein the characteristic of the magnetic noise isinfluenced by a presence or absence of one or more MNPs at each of theplurality of sites.
 2. The sensing device of claim 1, wherein thecharacteristic is an amplitude of the magnetic noise at a particularfrequency or within a particular frequency band.
 3. The sensing deviceof claim 2, wherein the detection circuitry comprises: a bias elementcoupled to at least one of the plurality of MR sensors and configured togenerate a bias across the at least one of the plurality of MR sensors;a first low pass filter and amplifier combination coupled to the atleast one of the plurality of MR sensors to filter and amplify a signalfrom the at least one of the plurality of MR sensors; a referenceoscillator configured to generate a reference signal having a particularfrequency chosen to maximize a change in the signal at the particularfrequency when at least one of the one or more MNPs labeling aparticular molecule type is detected by the at least one of theplurality of MR sensors at one or more of the plurality of sites; amixer coupled to the reference oscillator and an output of the first lowpass filter and amplifier combination, wherein the mixer is configuredto mix an output signal from the first low pass filter and amplifiercombination with the reference signal; a second low pass filter andamplifier combination coupled to the mixer; and an envelope detectorconfigured to receive an output signal from the second low pass filterand amplifier combination and provide a signal for detection, wherein avoltage of the signal for detection is proportional to the amplitude ofthe magnetic noise.
 4. The sensing device of claim 1, wherein thecharacteristic is a fluctuation of the magnetic noise.
 5. The sensingdevice of claim 4, wherein the detection circuitry comprises: a biaselement coupled to at least one of the plurality of MR sensors andconfigured to generate a bias across the at least one of the pluralityof MR sensors; an amplifier coupled to the at least one of the pluralityof MR sensors to filter and amplify a signal from the at least one ofthe plurality of MR sensors; a filter coupled to the amplifier; and anenvelope detector configured to receive an output signal from the filterand provide a signal for detection, wherein a voltage of the signal fordetection is proportional to the fluctuation of the magnetic noise. 6.The sensing device of claim 1, wherein the characteristic is a phase ofthe magnetic noise.
 7. The sensing device of claim 6, wherein thedetection circuitry comprises a phase locked loop configured to providean error signal output that corresponds to the phase of the magneticnoise.
 8. The sensing device of claim 1, further comprising: a pluralityof lines coupled to the plurality of MR sensors; and a plurality ofselector elements, each of the plurality of selector elements coupled toat least one of the plurality of lines and to a respective one of theplurality of MR sensors.
 9. The sensing device of claim 8, wherein theplurality of selector elements comprises a transistor.
 10. The sensingdevice of claim 8, wherein the plurality of selector elements comprisesan in-stack selector element.
 11. The sensing device of claim 1, whereinthe sensing device is a sequencing device, and wherein the molecules arebiologic molecules.
 12. The sensing device of claim 11, wherein thebiologic molecules are nucleic acid molecules.
 13. The sensing device ofclaim 1, wherein at least one of the MR sensors comprises a pinnedlayer, a free layer, and a spacer layer disposed between the pinnedlayer and the free layer, and wherein, absent an applied magnetic fieldand absent the presence of one or more MNPs, an orientation of amagnetic moment of the free layer is approximately 90° from anorientation of a magnetic moment of the pinned layer.
 14. The sensingdevice of claim 1, wherein: a first subset of the plurality of MRsensors is arranged in a first row; a second subset of the plurality ofMR sensors is arranged in a second row, the second row being parallel tothe first row; and the at least one fluidic channel is disposed betweenthe first and second rows.
 15. The sensing device of claim 1, furthercomprising a selector element.
 16. The sensing device of claim 15,wherein the selector element comprises a transistor.
 17. The sensingdevice of claim 15, wherein the selector element is an in-stack selectorelement.
 18. The sensing device of claim 1, further comprising amagnetic component configured to apply a magnetic field across thesensing device.
 19. The sensing device of claim 18, wherein the magneticcomponent comprises one or more of an electromagnet, a distributed coil,a solenoid, a permanent magnet, or a super-conducting magnet.
 20. Amethod of using the sensing device of claim 1, comprising: applying amagnetic field across the sensing device; and the detection circuitrydetecting the characteristic of the magnetic noise of each of theplurality of MR sensors.
 21. The method of claim 20, wherein, in avicinity of each of the plurality of MR sensors, the applied magneticfield is (a) in a substantially same direction as a field emanating fromthe one or more MNPs, or (b) in a substantially opposite direction fromthe field emanating from the one or more MNPs.
 22. A method offabricating the sensing device of claim 1, wherein at least one of theMR sensors comprises a pinned layer, a free layer, and a spacer layerdisposed between the pinned layer and the free layer, and wherein anorientation of a magnetic moment of the free layer is approximately 90°from an orientation of a magnetic moment of the pinned layer, andwherein the method comprises at least one of: applying a hard biasfield; patterning the at least one of the MR sensors into a rectangle orellipse; etching the free and pinned layers along an axis to inducetexturing; or using perpendicular magnetic anisotropy to pull the freelayer out of plane while keeping the pinned layer in the plane of the atleast one of the MR sensors.
 23. A sensing device, comprising: at leastone fluidic channel configured to receive a plurality of molecules to bedetected, wherein at least some of the plurality of molecules to bedetected are coupled to respective magnetic nanoparticles (MNPs); aplurality of magnetoresistive (MR) sensors; an insulating materialencapsulating the plurality of MR sensors and for providing a barrierbetween the plurality of MR sensors and a contents of the at least onefluidic channel; and detection circuitry coupled to each of theplurality of MR sensors, wherein: a surface of the insulating materialwithin the fluidic channel provides a plurality of sites for binding theplurality of molecules to be detected, the plurality of sites beinglocated among the plurality of MR sensors, and the detection circuitryis configured to detect one or more of a change in resistance, current,or voltage drop across each of the plurality of MR sensors, wherein thechange in resistance, current, or voltage drop is influenced by thepresence or absence of one or more MNPs at each of the plurality ofsites.
 24. The sensing device of claim 23, wherein the detectioncircuitry is further configured to report the change in resistance,current, or voltage drop as a binary output that indicates the presenceor absence of a particular MNP labeling a particular molecule type ateach of the plurality of sites.
 25. The sensing device of claim 23,wherein the detection circuitry is further configured to report thechange in resistance, current, or voltage drop at each of the pluralityof sites as a quantized output having one of a plurality of levels, atleast some of the levels being used to differentiate MNPs havingdifferent saturation magnetizations, with each saturation magnetizationcorresponding to a particular MNP labeling a particular molecule type.26. The sensing device of claim 23, further comprising: a plurality oflines coupled to the plurality of MR sensors; and a plurality ofselector elements, each of the plurality of selector elements coupled toat least one of the plurality of lines and to a respective one of theplurality of MR sensors.
 27. The sensing device of claim 26, wherein theplurality of selector elements includes a transistor.
 28. The sensingdevice of claim 26, wherein the plurality of selector elements comprisesan in-stack selector element.
 29. The sensing device of claim 23,wherein the sensing device is a sequencing device, and wherein themolecules are biologic molecules.
 30. The sensing device of claim 29,wherein the biologic molecules are nucleic acid molecules.
 31. Thesensing device of claim 23, wherein each of the MR sensors comprises apinned layer, a free layer, and a spacer layer disposed between thepinned layer and the free layer, and wherein, absent an applied magneticfield and absent the presence of one or more MNPs, an orientation of amagnetic moment of the free layer is approximately 90° from anorientation of a magnetic moment of the pinned layer.
 32. The sensingdevice of claim 23, wherein: a first subset of the plurality of MRsensors is arranged in a first row; a second subset of the plurality ofMR sensors is arranged in a second row, the second row being parallel tothe first row; and the at least one fluidic channel is disposed betweenthe first and second rows.
 33. The sensing device of claim 23, furthercomprising a selector element.
 34. The sensing device of claim 33,wherein the selector element comprises a transistor.
 35. The sensingdevice of claim 33, wherein the selector element is an in-stack selectorelement.
 36. A method of fabricating the sensing device of claim 23,wherein at least one of the MR sensors comprises a pinned layer, a freelayer, and a spacer layer disposed between the pinned layer and the freelayer, and wherein an orientation of a magnetic moment of the free layeris approximately 90° from an orientation of a magnetic moment of thepinned layer, and wherein the method comprises at least one of: applyinga hard bias field; patterning the at least one of the MR sensors into arectangle or ellipse; etching the free and pinned layers along an axisto induce texturing; or using perpendicular magnetic anisotropy to pullthe free layer out of plane while keeping the pinned layer in the planeof the at least one of the MR sensors.